title: Rescue of severe infantile hypophosphatasia mice by AAV-mediated sustained expression of soluble alkaline phosphatase.
abstract: Hypophosphatasia (HPP) is an inherited disease caused by a deficiency of tissue-nonspecific alkaline phosphatase (TNALP). The major symptom of human HPP is hypomineralization, rickets, or osteomalacia, although the clinical severity is highly variable. The phenotypes of TNALP knockout (Akp2(-/-)) mice mimic those of the severe infantile form of HPP. Akp2(-/-) mice appear normal at birth, but they develop growth failure, epileptic seizures, and hypomineralization and die by 20 days of age. Previously, we have shown that the phenotype of Akp2(-/-) mice can be prevented by enzyme replacement of bone-targeted TNALP in which deca-aspartates are linked to the C-terminus of soluble TNALP (TNALP-D10). In the present study, we evaluated the therapeutic effects of adeno-associated virus serotype 8 (AAV8) vectors that express various forms of TNALP, including TNALP-D10, soluble TNALP tagged with the Flag epitopes (TNALP-F), and native glycosylphosphatidylinositol-anchored TNALP (TNALP-N). A single intravenous injection of 5×10(10) vector genomes of AAV8-TNALP-D10 into Akp2(-/-) mice at day 1 resulted in prolonged survival and phenotypic correction. When AAV8-TNALP-F was injected into neonatal Akp2(-/-) mice, they also survived without epileptic seizures. Interestingly, survival effects were observed in some animals treated with AAV8-TNALP-N. All surviving Akp2(-/-) mice showed a healthy appearance and a normal activity with mature bone mineralization on X-rays. These results suggest that sustained alkaline phosphatase activity in plasma is essential and sufficient for the rescue of Akp2(-/-) mice. AAV8-mediated systemic gene therapy appears to be an effective treatment for the infantile form of human HPP.
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Tae
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyake
authors.forename: Seiko
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hideo
authors.initials: H
authors.lastname: Orimo
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Yuko
authors.initials: Y
authors.lastname: Odagaki
authors.forename: Kumi
authors.initials: K
authors.lastname: Adachi
authors.forename: Osamu
authors.initials: O
authors.lastname: Iijima
authors.forename: Sonoko
authors.initials: S
authors.lastname: Narisawa
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D007014:Hypophosphatasia / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase